A protein having a basic helix-loop-helix (hereinafter referred to as bHLH) motif and a PAS domain (Per-Arnt-Sim homology domain) (such protein hereinafter being referred to as bHLH-PAS protein) binds to a DNA by forming a homodimer or a heterodimer to act as a transcription regulatory factor, whereby playing an important role in the transcriptional regulation of a gene involved in the cell proliferation, development and differentiation, as well as biological function exertion (Annu Rev Pharmacol Toxicol 2000; 40:519–61).
For example, an Ah receptor (aryl hydrocarbon receptor) is activated as a result of the binding of a ligand such as a dioxin to form a heterodimer with an Arnt (AhR nuclear translocator) which is also a bHLH-PAS protein, whereby binding to a transcription regulatory region for example of a drug metabolism enzyme gene, whose transcription is thus activated. An Hif activate the gene expression in a biological response under a hypoxic condition, while Per and Clock are involved in a circadian rhythm control and SRC-1 and TIF2 serve as coactivators of a steroidal hormone receptor family. Since a Sim involved in the development of the median line in a fruit fly is expressed in the median line during the development process also in a mammalian animal such as human, it is considered to be involved in the development of the latter, and a human Sim2 is suggested to be involved also in a genetic disease Down's syndrome (Genome Res 1997; 7:615–624, Chrast, R et al). In addition, NPAS1 and NPAS2 expressed mainly in the central nervous system in an adult are suggested to be involved in a mouse genetic disease exhibiting an abnormality in the nervous functions or behaviors (Proc. Natl. Acad. Sci. USA 1997; 94:713–18), and a knockout mouse whose NPAS 2 gene has been destroyed exhibited an abnormality in a long-term memory (Science 2000; 288:2226–2230).
Thus, a bHLH-PAS protein, in a tissue where it is expressed, is involved in the transcriptional regulation of a gene such as an enzyme gene or structural gene necessary for the development of the such a tissue as well as the exertion of the function, and its malfunction leads to a disease or disorder. Accordingly, in order to develop a means useful in the diagnosis, prophylaxis and therapy of such a disease or disorder, it is highly desirable to obtain a bHLH-PAS protein and a DNA encoding such a protein.